Consumer medicine information

Symdeko

Tezacaftor; Ivacaftor

BRAND INFORMATION

Brand name

Symdeko

Active ingredient

Tezacaftor; Ivacaftor

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Symdeko.

SUMMARY CMI

SYMDEKO®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details. Read before using this medicine.

1. Why am I using SYMDEKO?

SYMDEKO contains the active ingredients tezacaftor and ivacaftor. SYMDEKO is used for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is listed in the approved indication. For more information, see Section 1. Why am I using SYMDEKO? in the full CMI.

2. What should I know before I use SYMDEKO?

Do not use if you have ever had an allergic reaction to SYMDEKO or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use SYMDEKO? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with SYMDEKO and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use SYMDEKO?

Your doctor will tell you how much SYMDEKO you need to take each day. This may depend on your condition and whether or not you are taking other medicines. SYMDEKO is for oral use. More instructions can be found in Section 4. How do I use SYMDEKO? in the full CMI.

5. What should I know while using SYMDEKO?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using SYMDEKO.
  • Use SYMDEKO exactly as your doctor has prescribed.
  • Take SYMDEKO with fat-containing food and avoid food or drinks containing grapefruit or Seville Oranges.
  • Tell your doctor if you become pregnant while using SYMDEKO.
Things you should not do
  • Do not stop using SYMDEKO or change the dose without first checking with your doctor.
  • Do not take any other medicines whether they require a prescription or not without first telling your doctor or consulting a pharmacist.
Looking after your medicine
  • Store below 30°C, in a dry place away from moisture, heat or sunlight.
  • Keep this medicine where young children cannot reach it.

For more information, see Section 5. What should I know while using SYMDEKO? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention. Ask your doctor or pharmacist if you have any further questions about side effects.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking SYMDEKO.

Some common side effects experienced by patients taking SYMDEKO include the headache, throat and nose infections.

If you experience significant pain or discomfort in the upper right stomach (abdominal) area, or yellowing of your skin or the white parts of your eyes these may be indicative of serious side effects.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

SYMDEKO® (SIM-deh-koh)

Active ingredient(s): Tezacaftor/ Ivacaftor, Ivacaftor

Consumer Medicine Information (CMI)

This leaflet provides important information about using SYMDEKO. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using SYMDEKO.

Where to find information in this leaflet:

1. Why am I using SYMDEKO?
2. What should I know before I use SYMDEKO?
3. What if I am taking other medicines?
4. How do I use SYMDEKO?
5. What should I know while using SYMDEKO?
6. Are there any side effects?
7. Product details

1. Why am I using SYMDEKO?

SYMDEKO contains the active ingredients Tezacaftor, Ivacaftor.

SYMDEKO is used for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is listed in the approved indication.

SYMDEKO belongs to a group of medicines called “cystic fibrosis transmembrane conductance regulator (CFTR) modulators”. SYMDEKO includes two types of tablets, one contains tezacaftor and ivacaftor (morning dose) and the other contains ivacaftor (evening dose).

Tezacaftor is a “CFTR corrector” and works to increase the amount of protein at the cell surface.

Ivacaftor is a “CFTR potentiator” that makes the protein work better once it reaches the cell surface.

SYMDEKO is not addictive.

What is cystic fibrosis?

Cystic fibrosis is caused by genetic defects that limit the flow of chloride and water through cell membranes. As a result, the mucus in the lungs (and other organs) becomes thick and sticky, clogging the lungs and making it easier for germs to grow. SYMDEKO is a medicine that works by improving the flow of chloride and water in patients with cystic fibrosis who have a certain genetic defect.

2. What should I know before I use SYMDEKO?

Warnings

Do not use SYMDEKO if:

  • you are allergic to tezacaftor, ivacaftor, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is unknown whether SYMDEKO is excreted in human milk. If you plan to breast-feed, ask your doctor for advice before taking SYMDEKO.

Use in children

Do not give SYMDEKO to children under 6 years of age.

It is not known if SYMDEKO is safe and effective in children under 6 years of age.

Tell your doctor if you:

  • have kidney disease or kidney problems in the past.
  • have liver disease or you have had liver problems in the past.
  • have received an organ transplant.

Laboratory Testing

Your doctor will do some blood tests to check your liver prior to and while you are taking SYMDEKO, particularly during the first year and especially if you have had high liver enzymes in the past. Increased liver enzymes in the blood have been seen in some people receiving SYMDEKO.

Your doctor may need to adjust your dose of SYMDEKO or monitor your blood tests for liver enzymes.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may be affected by SYMDEKO or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor will advise you.

Take SYMDEKO with fat-containing food and avoid food or drinks containing grapefruit or Seville oranges.

Tell your doctor or pharmacist if you are taking any of the following:

Antifungal medicines used for the treatment of fungal infectionsketoconazole, itraconazole, posaconazole, voriconazole, fluconazole
Antibiotic medicines used for treatment of bacterial infectionstelithromycin, clarithromycin, erythromycin, rifampicin, rifabutin, ciprofloxacin
Anticonvulsant medicines used for the treatment of epileptic seizuresphenobarbital, carbamazepine, phenytoin
Herbal medicineSt. John's wort (Hypericum perforatum)
Benzodiazepines used for the treatment of anxiety, insomnia, agitation, etcmidazolam
Immunosuppressants used after organ transplantationciclosporin, everolimus, sirolimus, tacrolimus
Cardiac glycosides used for the treatment of congestive heart failure and an abnormal heart rhythmdigoxin
Anticoagulants used to prevent blood clots from forming or growing larger in blood and blood vesselswarfarin
Medicines for diabetesglimepiride, glipizide
Medicines for lowering blood cholesterolpitavastatin

Your doctor or pharmacist has more information on medicines to be careful with or to avoid while taking SYMDEKO.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect SYMDEKO.

4. How do I use SYMDEKO?

How much to take

Your doctor will tell you how much SYMDEKO you need to take each day. This may depend on your condition and whether or not you are taking other medicines.

SYMDEKO dosing recommendations are as follows:

Patients aged 6 to <12 years weighing <30 kg

Morning dose:

One white tablet tezacaftor 50 mg/ivacaftor 75 mg

Evening dose:

One light blue tablet ivacaftor 75 mg

Patients aged 6 to <12 years weighing ≥30 kg

Morning dose:

One yellow tablet tezacaftor 100 mg/ivacaftor 150 mg

Evening dose:

One light blue tablet ivacaftor 150 mg

Patients aged ≥12 years

Morning dose:

One yellow tablet tezacaftor 100 mg/ivacaftor 150 mg

Evening dose:

One light blue tablet ivacaftor 150 mg

If you have liver problems, your doctor may need to reduce the dose as your liver is not clearing ivacaftor and tezacaftor as fast as in people who do not have liver problems.

Follow all instructions given by your doctor, or health care professional.

When to take SYMDEKO

  • SYMDEKO should be used every day and continue taking it for as long as your doctor tells you.
  • Your doctor will determine if your treatment should be stopped.

How to take SYMDEKO

SYMDEKO is for oral use.

Do not break, chew or dissolve the tablets. Swallow the tablets whole.

Tablets

  • Take 1 white (tezacaftor 50 mg/ ivacaftor 75 mg) or yellow tablet (tezacaftor 100mg/ivacaftor 150mg) in the morning with a fat-containing meal or snack. Avoid food containing grapefruit or Seville oranges.
  • Take 1 light blue tablet (ivacaftor 75 mg or ivacaftor 150 mg) about 12 hours later in the evening with a fat containing meal or snack. Avoid food containing grapefruit or Seville oranges.

Examples of meals or snacks that contain fat are those prepared with butter or oils or those containing eggs.

Other fat-containing foods are:

  • Cheese, whole milk, whole-milk dairy products, yoghurt, chocolate
  • Meats, oily fish
  • Avocados, hummus, soy-based products (tofu)
  • Nuts, fat-containing nutritional bars or drinks

If you forget to use SYMDEKO

SYMDEKO should be used regularly at the same time each day.

Take the missed dose if less than 6 hours have passed since the time you missed the dose. Otherwise, wait until your next scheduled dose as you normally would.

Do not take a double dose to make up for the dose you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, talk to your doctor or pharmacist.

If you take too much SYMDEKO

If you think that you have used too much SYMDEKO, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using SYMDEKO?

Things you should do

Keep all of your doctor's appointments so that your progress can be checked.

  • Use SYMDEKO exactly as your doctor has prescribed.
  • Take SYMDEKO with fat-containing food and avoid food or drinks containing grapefruit.
  • Tell your doctor if you become pregnant while using SYMDEKO.
  • Tell your doctor if, for any reason, you have not used SYMDEKO exactly as prescribed.
  • Your doctor may perform some eye examinations prior to and during treatment with SYMDEKO. Abnormality of the eye lens (cataract) without any effect on vision has been noted in some patients receiving this treatment.

Remind any doctor, dentist or pharmacist you visit that you are using SYMDEKO.

Things you should not do

  • Do not stop using SYMDEKO or change the dose without first checking with your doctor.
  • Do not let yourself run out of medicine over the weekend or on holidays.
  • Do not give SYMDEKO to anyone else even if they have the same condition as you.
  • Do not use SYMDEKO to treat other complaints unless your doctor tells you to.
  • Do not take any other medicines whether they require a prescription or not without first telling your doctor or consulting a pharmacist.

Things to be careful of

Avoid food or drinks containing grapefruit or Seville oranges during treatment with SYMDEKO as this may increase the amount of SYMDEKO in your body.

SYMDEKO contains lactose. If you have been told by your doctor that you have intolerance to some sugars, contact your doctor before taking this medicine.

Driving or using machines

SYMDEKO can make you dizzy. Do not drive or use machines unless you are sure that you are not affected.

If your child is taking SYMDEKO it is advised that he/she does not ride his/her bike or do anything else that needs his/ her full attention unless you are sure that your child is not affected.

Looking after your medicine

  • Store below 30°C. Store in original container.
  • Keep this medicine where young children cannot reach it.

Do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Follow the instructions in the carton on how to take care of your medicine properly.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking SYMDEKO.

Less serious side effects

Less serious side effectsWhat to do

Very common side effects (may affect more than 1 in 10 people)

  • Headache
  • Throat and nose infections

Common side effects (may affect up to 1 in 10 people)

  • Feeling sick (nausea)
  • Sinus congestion
  • Dizziness
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
The following may be indicative of serious side effects associated with your liver.
You may need urgent medical attention if you experience:
  • significant pain or discomfort in the upper right stomach (abdominal) area.
  • yellowing of your skin or the white parts of your eyes.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Serious side effects are uncommon.

This is not a complete list of all possible side effects. Your doctor or pharmacist has a more complete list.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell, even if it is not on this list.

Other side effects not listed here may occur in some people and there may be some side effects not yet known.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What SYMDEKO contains
Morning dose (SYMDEKO 50 mg/75 mg or SYMDEKO 100 mg/150 mg)

Active ingredient
(main ingredient)		Tezacaftor, Ivacaftor
Other ingredients
(inactive ingredients)		Hypromellose acetate succinate
Sodium lauryl sulfate
Hypromellose
Microcrystalline cellulose
Croscarmellose sodium
Magnesium stearate
Film coating:
50/75 mg tablets: Opadry complete film coating system 20A180008 White (PI No. 139612)
100/150 mg tablets: Opadry complete film coating system 20A120010 Yellow (PI No. 111630)

Evening dose (ivacaftor 75 mg or 150 mg)

Active ingredient
(main ingredient)		Ivacaftor
Other ingredients
(inactive ingredients)		Microcrystalline cellulose
Lactose monohydrate
Hypromellose acetate succinate
Croscarmellose sodium
Sodium lauryl sulfate
Silicon dioxide
Magnesium stearate
Carnauba wax
Film coating:
OPACODE monogramming ink S-1-17823 BLACK (PI No. 12108)
75 mg: Opadry II complete film coating system 85F105098 Blue (PI No. 140157)
150 mg: Opadry II complete film coating system 85F90614 Blue (PI No. 108371)
Potential allergensLactose monohydrate

Do not take this medicine if you are allergic to any of these ingredients.

What SYMDEKO looks like
SYMDEKO 50 mg/75 mg and ivacaftor 75 mg

Morning dose

White, capsule-shaped tablet debossed with “V50” on one side and plain on the other (12.70 mm x 6.78 mm).

Evening dose

Light blue, capsule-shaped tablet, printed with “V 75” in black ink on one side and plain on the other (12.70 mm x 6.87 mm).

SYMDEKO 100 mg/150 mg and ivacaftor 150 mg

Morning dose

Yellow, capsule-shaped tablet debossed with “V100” on one side and plain on the other

(15.9 mm x 8.5 mm).

Evening dose

Light blue, capsule-shaped tablet, printed with “V150” in black ink on one side and plain on the other (16.5 mm x 8.4 mm).

SYMDEKO 50 mg/75 mg is Aust R 337367.
SYMDEKO 100 mg/150 mg is Aust R 298329.

Availability

SYMDEKO tablets are available in the following pack size:

  • blister pack containing 56 film-coated tablets (28 tablets containing both tezacaftor and ivacaftor (morning dose) and 28 tablets containing ivacaftor (evening dose)).

SYMDEKO tablets are available in the following strength:

  • SYMDEKO 50 mg/75 mg: tezacaftor 50 mg/ ivacaftor 75 mg and;
    ivacaftor 75 mg
  • SYMDEKO 100 mg/150 mg: tezacaftor 100 mg/ ivacaftor 150 mg and;
    ivacaftor 150 mg

Who distributes SYMDEKO

Vertex Pharmaceuticals (Australia) Pty Ltd
Suite 3, Level 3
601 Pacific Highway
St Leonards
NSW 2065
Australia

This leaflet was prepared in April 2021.

©2021 Vertex Pharmaceuticals Incorporated

SYMDEKO, VERTEX and the VERTEX triangle logo are registered trademarks of Vertex Pharmaceuticals Incorporated.

Published by MIMS June 2021

BRAND INFORMATION

Brand name

Symdeko

Active ingredient

Tezacaftor; Ivacaftor

Schedule

S4

 

1 Name of Medicine

Tezacaftor and ivacaftor in combination; and ivacaftor.

2 Qualitative and Quantitative Composition

Symdeko 50 mg/75 mg + 75 mg film-coated tablets.

Morning dose.

Tezacaftor/ivacaftor 50 mg/75 mg.

Evening dose.

Ivacaftor 75 mg.

Symdeko 100 mg/150 mg + 150 mg film-coated tablets.

Morning dose.

Tezacaftor/ivacaftor 100 mg/150 mg.

Evening dose.

Ivacaftor 150 mg.

Excipients with known effect.

Sugars as lactose (for 150 mg Ivacaftor tablet).
Lactose (for 75 mg Ivacaftor tablet).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Composite pack.

Symdeko 50 mg/75 mg + 75 mg film-coated tablets.

Morning dose.

Tezacaftor/ivacaftor 50 mg/75 mg.
White, capsule shaped tablet debossed with "V50" on one side and plain on the other (12.70 mm x 6.78 mm).

Evening dose.

Ivacaftor 75 mg film-coated tablets.
Light blue, capsule-shaped tablet, printed with "V 75" in black ink on one side and plain on the other (12.70 mm x 6.87 mm).
Symdeko 100 mg/150 mg + 150 mg film-coated tablets.

Morning dose.

Tezacaftor/ivacaftor 100 mg/150 mg.
Yellow, capsule shaped tablet debossed with "V100" on one side and plain on the other (15.9 mm x 8.5 mm).

Evening dose.

Ivacaftor 150 mg film-coated tablets.
Light blue, capsule-shaped tablet, printed with "V150" in black ink on one side and plain on the other (16.5 mm x 8.4 mm).

4 Clinical Particulars

4.1 Therapeutic Indications

Symdeko is indicated for the treatment of patients with cystic fibrosis (CF) aged 6 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence.
See Table 1 for a list of responsive mutations.

4.2 Dose and Method of Administration

Symdeko should only be prescribed by physicians with experience in the treatment of CF. If the patient's genotype is unknown, an accurate and validated genotyping method should be performed to confirm the presence of an indicated mutation (see Table 1).
Table 1 lists mutations that are responsive to tezacaftor/ivacaftor based on positive clinical response and/or in-vitro data obtained from FRT cells (see Section 5.1 Pharmacodynamic Properties).

Dosage.

Adults, adolescents and children ages 6 years and older should be dosed according to Table 2.
The morning and evening dose should be taken with fat-containing food, approximately 12 hours apart.

Missed dose.

If 6 hours or less have passed since a missed morning or evening dose, the patient should take the missed dose as soon as possible and continue on the original schedule.
If more than 6 hours have passed since the missed morning or evening dose, the patient should not take the missed dose. The next scheduled dose should be taken at the usual time.
More than one dose should not be taken at the same time.

Method of administration.

For oral use. Patients should be instructed to swallow the tablets whole.
A fat-containing meal or snack should be consumed just before or just after dosing of Symdeko. Meals and snacks recommended in CF guidelines or meals recommended in standard nutritional guidelines contain adequate amounts of fat. A serving size of foods appropriate for age from a typical CF diet should be given. Examples of meals or snacks that contain fat are those prepared with butter or oils or those containing eggs, cheeses, nuts, chocolate, whole milk, whole-milk dairy products, meats, avocados, oily fish, and soy-based products (tofu) (see Section 5.2 Pharmacokinetic Properties).
Food or drink containing grapefruit or Seville oranges should be avoided during treatment with Symdeko (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Dosage adjustment.

Hepatic impairment.

For dose adjustment for patients with hepatic impairment, see Table 3. There is no experience in patients with severe hepatic impairment (Child-Pugh Class C); the exposure of tezacaftor and ivacaftor in these patients is expected to be higher than in patients with moderate hepatic impairment. Therefore, caution is recommended in these patients. After weighing the risks and benefits of treatment, Symdeko should be used with caution at a reduced dose (see Section 5.2 Pharmacokinetic Properties).

Renal impairment.

No dose adjustment is recommended for mild and moderate renal impairment. Caution is recommended in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease (see Section 5.2 Pharmacokinetic Properties).

Concomitant use of CYP3A inhibitors.

The dose of Symdeko should be adjusted when co-administered with moderate and strong CYP3A inhibitors (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
When co-administered with moderate inhibitors of CYP3A (e.g. fluconazole, erythromycin), or when co-administered with strong inhibitors of CYP3A (e.g. ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin), the dose should be adjusted as in Table 4 (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.3 Contraindications

In cases of hypersensitivity to the active substance or to any component of this medication, patients should not be treated with this medicine.

4.4 Special Warnings and Precautions for Use

Cataracts.

Cases of non-congenital lens opacities without impact on vision have been reported in paediatric patients treated with Symdeko, as well as with ivacaftor monotherapy. Although other risk factors were present in some cases (such as corticosteroid use, exposure to radiation) a possible risk attributable to treatment with Symdeko cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in paediatric patients initiating treatment with Symdeko (see Section 5.3 Preclinical Safety Data).
Cataracts were seen in juvenile rats treated with ivacaftor from postnatal Day 7 through 35 at oral dose levels of 10 mg/kg/day and higher, yielding exposure to ivacaftor and its major metabolites approximately 3-5 times lower than in patients at the maximum recommended human dose of Symdeko (based on summed AUCs). This finding has not been observed in older animals. The potential relevance of these findings in humans is unknown.

Interactions with other medicinal products.

CYP3A inducers.

Exposure to tezacaftor and ivacaftor may be reduced by the concomitant use of CYP3A inducers, potentially resulting in the reduction of Symdeko efficacy; therefore, co-administration with strong CYP3A inducers is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

CYP3A inhibitors.

The dose of Symdeko should be adjusted when used concomitantly with strong or moderate CYP3A inhibitors (see Section 4.2 Dose and Method of Administration, Table 4).

Effect on liver function tests.

Elevated transaminases are common in patients with CF, and have been observed in some patients treated with Symdeko, as well as with ivacaftor monotherapy. Assessments of transaminases (ALT and AST) are recommended for all patients prior to initiating Symdeko, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations, more frequent monitoring should be considered. In the event of significant elevations of transaminases e.g. patients with ALT or AST > 5x upper limit of normal (ULN), or ALT or AST > 3 x ULN with bilirubin > 2 x ULN, dosing should be interrupted and laboratory tests closely followed until the abnormalities resolve. Following the resolution of transaminase elevations, consider the benefits and risks of resuming treatment (see Section 4.8 Adverse Effects (Undesirable Effects)).

Patients after organ transplantation.

Symdeko has not been studied in patients with CF who have undergone organ transplantation. Therefore, use in transplanted patients is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions for interactions with ciclosporin or tacrolimus).

Use in elderly.

Clinical trials of Symdeko did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients.

Paediatric use.

The safety and efficacy of Symdeko in children aged less than 6 years has not yet been studied (see Section 5.1 Pharmacodynamic Properties).

Effects on laboratory tests.

See Section 4.4 Special Warnings and Precautions for Use, Effect on liver function tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Medicinal products affecting the pharmacokinetics of Symdeko.

CYP3A inducers.

Tezacaftor and ivacaftor are substrates of CYP3A (ivacaftor is a sensitive substrate of CYP3A). Concomitant use of CYP3A inducers may result in reduced exposures and thus reduced Symdeko efficacy. Co-administration of ivacaftor with rifampicin, a strong CYP3A inducer, significantly decreased ivacaftor exposure (area under the curve [AUC]) by 89%. Tezacaftor exposures can also be expected to decrease significantly during co-administration with strong CYP3A inducers; therefore, co-administration of Symdeko with strong CYP3A inducers is not recommended.
Examples of strong CYP3A inducers include: rifampicin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John's wort (Hypericum perforatum).

CYP3A inhibitors.

Co-administration with itraconazole, a strong CYP3A inhibitor, increased tezacaftor exposure (measured as AUC) by 4.0-fold and increased ivacaftor AUC by 15.6-fold. When co-administered with strong CYP3A inhibitors, the dose of Symdeko should be reduced (see Section 4.2 Dose and Method of Administration, Table 4).
Examples of strong CYP3A inhibitors include:
ketoconazole, itraconazole, posaconazole, and voriconazole;
telithromycin and clarithromycin.
Physiologically based pharmacokinetic modeling suggested co-administration with fluconazole, a moderate CYP3A inhibitor, may increase tezacaftor exposure (AUC) by approximately 2-fold. Co-administration of fluconazole increased ivacaftor AUC by 3-fold. When co-administered with moderate CYP3A inhibitors, the dose of Symdeko should be reduced (see Section 4.2 Dose and Method of Administration, Table 4).
Examples of moderate CYP3A inhibitors include: fluconazole; erythromycin.
Co-administration of Symdeko with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ivacaftor and tezacaftor; therefore, food or drink containing grapefruit or Seville oranges should be avoided during treatment with Symdeko (see Section 4.2 Dose and Method of Administration).
No dose adjustment is necessary for Symdeko when administered concomitantly with ciprofloxacin.

Medicinal products affected by Symdeko.

CYP3A substrates.

Co-administration with (oral) midazolam, a sensitive CYP3A substrate, did not affect midazolam exposure. No dose adjustment of CYP3A substrates is required when co-administered with Symdeko.

CYP2C9 substrates.

Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalised ratio (INR) during co-administration of Symdeko with warfarin is recommended. Other drugs for which exposure may be increased by Symdeko include glimepiride and glipizide; these drugs should be used with caution.

Digoxin and other P-gp substrates.

Co-administration of Symdeko with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold, consistent with weak inhibition of P-gp by ivacaftor. Administration of Symdeko may increase systemic exposure of medicinal products that are sensitive substrates of P-gp, which may increase or prolong their therapeutic effect and adverse reactions. When used concomitantly with digoxin or other substrates of P-gp with a narrow therapeutic index such as ciclosporin, everolimus, sirolimus, and tacrolimus, caution and appropriate monitoring should be used.

Hormonal contraceptives.

Symdeko has been studied with an oestrogen/progesterone oral contraceptive and was found to have no significant effect on the exposures of the hormonal contraceptive. Symdeko is not expected to modify the efficacy of hormonal contraceptives.

OATP1B1 substrates.

Symdeko has been studied with pitavastatin, an OATP1B1 substrate, and was found to have no clinically relevant effect on the exposure of pitavastatin. No dose adjustment of OATP1B1 substrates is required when co-administered with Symdeko.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Tezacaftor did not affect fertility or reproductive performance indices in male and female rats at oral doses up to 100 mg/kg/day (yielding systemic exposure in animals approximately 3 times greater than that in patients at the maximum recommended human dose [MRHD] based on summed AUCs of tezacaftor and its pharmacologically active M1-TEZ metabolite).
Ivacaftor impaired fertility and reproductive performance indices in male and female rats at an oral dose of 200 mg/kg/day (yielding approximately 12 and 6 times, respectively, the systemic exposure anticipated in patients at the MRHD based on summed AUCs of ivacaftor and its major metabolites when dams were dosed prior to and during early pregnancy. The pregnancy rate was decreased, oestrus cycling was disrupted and pre-implantation loss was increased. These effects occurred in the presence of significant maternal toxicity. No effects on male or female fertility and reproductive performance indices were observed at ≤ 100 mg/kg/day (yielding approximately 6.5 and 4 times, respectively, the exposure at the MRHD of the ivacaftor component of Symdeko based on summed AUCs of ivacaftor and its metabolites).
(Category B3)
Category B3 drugs have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed.
Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.
Tezacaftor, ivacaftor and/or their metabolites were shown to cross the placenta in laboratory animal species (rats and/or rabbits).

Tezacaftor.

No evidence of harm to the fetus was observed with tezacaftor in a developmental toxicity study in rats at oral doses up to 100 mg/kg/day (yielding 3 times the exposure at the MRHD (based on summed AUCs for tezacaftor and its M1 metabolite). In the rabbit, lower fetal body weights were noted at an oral dose of 50 mg/kg/day (the highest dose tested; yielding exposure around the same as at the MRHD), which occurred in conjunction with significant maternotoxicity. However, no effects on embryofetal survival and no teratogenicity were observed with tezacaftor in the species. Fetal body weight was unaffected in rabbits at 25 mg/kg/day (yielding exposure 4 times lower than that at the MRHD based on summed AUCs of tezacaftor and its M1 metabolite).

Ivacaftor.

Developmental toxicity studies with ivacaftor revealed no teratogenicity in rats at oral doses up to 200 mg/kg/day (yielding 6 times the summed AUC for ivacaftor and its major metabolites anticipated in patients) or in rabbits at up to 100 mg/kg/day (relative exposure based on summed AUCs, ≥ 3.4). Fetal weight was decreased and the incidence of minor fetal skeletal abnormalities was increased in rats treated at 200 mg/kg/day; these effects were observed in conjunction with maternal toxicity.
No adequate and well-controlled studies of Symdeko in pregnant women have been conducted. Because animal reproduction studies are not always predictive of human response, Symdeko should be used during pregnancy only if the potential benefits outweigh the potential risks.
 Both tezacaftor and ivacaftor are excreted into the milk of lactating female rats. Exposure of 14C-tezacaftor and 14C-ivacaftor in milk was approximately 2 and 1.5 times, respectively, higher than in plasma (based on AUC0-24 h). Because it is not known if tezacaftor, ivacaftor, or their metabolites are excreted in human milk, Symdeko should be used during breastfeeding only if the potential benefit outweighs the potential risks to the infant.

4.7 Effects on Ability to Drive and Use Machines

Dizziness has been reported in patients receiving Symdeko, which could influence the ability to drive or operate machines (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients experiencing dizziness should be advised not to drive or operate machines until symptoms abate.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The safety profile of Symdeko is based on pooled data from three double-blind, placebo-controlled, Phase 3 clinical studies in patients with CF aged 12 years and older, including: a 24-week study in patients homozygous for the F508del mutation in the CFTR gene, a 8-week cross-over study in patients heterozygous for the F508del-CFTR mutation and a second mutation associated with residual CFTR activity and a 12-week study in patients heterozygous for the F508del mutation and a second mutation not responsive to tezacaftor/ivacaftor. In these studies, a total of 496 patients received at least one dose of Symdeko. The proportion of patients who discontinued study drug prematurely due to adverse events was 1.6% for Symdeko treated patients and 2.0% for placebo-treated patients. The safety profile of Symdeko also includes data from a 24 week interim analysis, from a 96-week open-label extension study.
The safety profile of Symdeko, including respiratory events (e.g. chest discomfort, dyspnea, and respiration abnormal), was generally similar across all subgroups of patients, including analysis by age, sex, baseline percent predicted FEV1 (ppFEV1), and geographic regions.
Table 5 shows adverse events with an incidence of at least 10% in any treatment group from three double-blind, placebo-controlled, Phase 3 clinical studies (8, 12, and 24 weeks of treatment).

Tabulated list of adverse reactions.

Table 6 shows adverse events occurring in ≥ 3% of Symdeko-treated patients and at a frequency higher than placebo by ≥ 1%. Adverse events for Symdeko are ranked under the MedDRA frequency classification: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).
Safety data from the following additional studies are consistent with the safety data from the placebo-controlled Phase 3 studies (Studies 106 (EVOLVE), 108 (EXPAND) and 107):
A 96-week long term safety and efficacy rollover study in 1042 patients age 12 years and older who were homozygous or heterozygous for the F508del CFTR mutation (Study 110 (EXTEND)).
A 24-week, open-label Phase 3 study in 70 patients aged 6 to less than 12 years who were either homozygous for the F508del mutation or heterozygous for the F508del mutation and a second mutation associated with residual CFTR activity (Study 113 Part B (ENTRUST)).
An 8-week, double-blind, parallel group Phase 3 study in 67 patients aged 6 to less than 12 years who were either homozygous for the F508del mutation or heterozygous for the F508del mutation and a second mutation associated with residual CFTR activity (Study 115 (EMBRACE)).

Detailed description of selected adverse events.

Laboratory abnormalities.

Transaminase elevations.

During the placebo-controlled Phase 3 studies (up to 24 weeks), the incidence of maximum transaminase (ALT or AST) > 8, > 5, or > 3 x ULN were similar between Symdeko-treated patients and placebo-treated patients; 0.2%, 1.0%, and 3.4% in Symdeko-treated patients, and 0.4%, 1.0%, and 3.4% in placebo-treated patients. One patient (0.2%) on Symdeko, and 2 patients (0.4%) on placebo permanently discontinued treatment for elevated transaminases. No Symdeko-treated patients experienced a transaminase elevation > 3 x ULN associated with elevated total bilirubin > 2 x ULN.
During the 24-week, open-label Phase 3 study in patients aged 6 to less than 12 years (Study 113 Part B (ENTRUST), the incidence of maximum transaminase (ALT or AST) > 8, > 5, and > 3 x ULN were 1.4%, 4.3%, and 10.0%, respectively. No Symdeko-treated patients experienced a transaminase elevation > 3 x ULN associated with elevated total bilirubin > 2 x ULN or discontinued Symdeko treatment due to transaminase elevations.

Studies in patients aged 6 through 11 years.

The safety of Symdeko in combination with ivacaftor was evaluated in 124 patients between 6 to less than 12 years of age.
The safety profile is generally consistent among children and adolescents and is also consistent with adult patients.
During the 24-week, open-label Phase 3 study in patients aged 6 to less than 12 years (Study 113 Part B (ENTRUST) n=70), the incidence of maximum transaminase (ALT or AST) > 8, > 5, and > 3 x ULN were 1.4%, 4.3%, and 10.0%, respectively. No Symdeko-treated patients experienced a transaminase elevation > 3 x ULN associated with elevated total bilirubin > 2 x ULN or discontinued Symdeko treatment due to transaminase elevations. One patient interrupted treatment due to elevated transaminases, and subsequently resumed Symdeko treatment successfully (see Section 4.4 Special Warnings and Precautions for Use) for management of elevated transaminases).

Post-marketing experience.

There are no relevant updates from the post-marketing experience.

Reporting suspected adverse effects.

Reporting of suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product.
Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

No specific antidote is available for overdose with Symdeko. Treatment of overdose consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

CF is caused by mutations in the CFTR gene that result in the reduced function and/or quantity of the functional CFTR protein (responsible for chloride transport) to the cell surface in multiple organs including the lungs and pancreas. This is associated with persistent lung infections and progressive lung damage, characteristic of the morbidity and mortality associated with CF.
Tezacaftor is a broad-acting CFTR corrector that facilitates the cellular processing and trafficking of normal or multiple mutant forms of CFTR (including F508del-CFTR) to increase the amount of functional CFTR protein delivered to the cell surface, resulting in increased chloride transport. Ivacaftor is a CFTR potentiator that potentiates the channel-open probability (or gating) of CFTR at the cell surface to increase chloride transport. For ivacaftor to function CFTR protein must be present at the cell surface. Ivacaftor can potentiate the CFTR protein delivered to the cell surface by tezacaftor, leading to a further enhancement of chloride transport than either agent alone. The combined effect of tezacaftor and ivacaftor is increased quantity and function of CFTR at the cell surface, resulting in increases in chloride transport, airway surface liquid height, and ciliary beat frequency. Symdeko targets the underlying cause of CF in patients who are homozygous for the F508del mutation or who have at least one tezacaftor/ivacaftor responsive mutation in the CFTR gene (see Table 1).

CFTR chloride transport assay in Fischer rat thyroid (FRT) cells expressing mutant CFTR.

In order to evaluate the response of mutant CFTR protein to tezacaftor/ivacaftor, chloride transport was determined in Ussing chamber electrophysiology studies using a panel of FRT cell lines transfected with individual CFTR mutations. Mutations that are responsive to tezacaftor/ivacaftor resulted in increases in chloride transport to at least 10% of untreated normal over baseline.

Clinical trials.

Pharmacodynamic effects.

Effects on sweat chloride.

In EVOLVE (Study 106; patients homozygous for the F508del mutation), the treatment difference between Symdeko and placebo in mean absolute change from baseline in sweat chloride through Week 24, was -10.1 mmol/L (95% CI: -11.4, -8.8; nominal P < 0.0001*).
In EXPAND (Study 108; patients heterozygous for the F508del mutation and a second mutation associated with residual CFTR activity), the treatment difference in mean absolute change from baseline in sweat chloride through Week 8 was -9.5 mmol/L (95% CI: -11.7, -7.3; nominal P < 0.0001*) between Symdeko and placebo, and -4.5 mmol/L (95% CI: -6.7, -2.3; nominal P < 0.0001*) between ivacaftor and placebo.
* Nominal p-value, based on hierarchical testing procedure.
In ENTRUST (Study 113 Part B; patients aged 6 to less than 12 years who were homozygous or heterozygous for the F508del mutation) mean absolute change in sweat chloride from baseline through Week 24 was -14.5 mmol/L (95% CI: -17.4, -11.6).
In EMBRACE (Study 115; patients aged 6 to less than 12 years who were homozygous or heterozygous for the F508del mutation and a second mutation associated with residual CFTR activity), the within treatment mean absolute change in sweat chloride from baseline at Week 8 was -12.3 mmol/L (95% CI: -15.3, -9.3; nominal P <0.0001). In subgroup analyses the mean absolute change was -12.9 mmol/L (95% CI: -16.0, -9.9) for patients with F/F and for patients with F/RF the mean absolute change was -10.9 mmol/L (95% CI: -20.8, -0.9).

ECG evaluation.

The effect of multiple doses of tezacaftor 100 mg and 300 mg once daily on QTc interval was evaluated in a double-blind randomised, placebo- and active-controlled study with parallel design with nested crossover cohorts for moxifloxacin and placebo in 96 healthy subjects. No meaningful changes in QTc interval were observed with tezacaftor 100 mg or 300 mg once-daily dose groups.
In a separate study, the effect of multiple doses of ivacaftor 150 mg and 450 mg twice daily on QTc interval was evaluated in a randomised, placebo- and active-controlled (moxifloxacin 400 mg), four-period, crossover QT study in 72 healthy subjects. No meaningful changes in QTc interval were observed with ivacaftor 150 mg or 450 mg twice-daily dose groups.
Efficacy. The efficacy of Symdeko in patients with CF was demonstrated in three Phase 3, double-blind, controlled studies entitled EVOLVE (Study 106), EXPAND (Study 108) and EMBRACE (Study 115), and one Phase 3, open-label extension study entitled EXTEND (Study 110) and one Phase 3, open-label study ENTRUST (Study 113 Part B).
Patients in EVOLVE, EXPAND, ENTRUST and EMBRACE continued on their standard-of-care CF therapies (e.g. bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline). Patients had a confirmed genotype of a protocol-specified CFTR mutation, and a confirmed diagnosis of CF.
Patients with a history of colonization with organisms associated with a more rapid decline in pulmonary status such as Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus, or who had 2 or more abnormal liver function tests at screening (ALT, AST, AP, GGT ≥ 3 x ULN or total bilirubin ≥ 2 x ULN) or AST or ALT ≥ 5 x ULN, were excluded from these studies.
EVOLVE - a study in patients with CF who were homozygous for the F508del mutation in the CFTR gene (study 106). EVOLVE (Study 106) was a 24-week, randomised, double-blind, placebo-controlled study. A total of 504 patients aged 12 years and older (mean age 26.3 years) who were homozygous for the F508del mutation in the CFTR gene were randomised (1:1 randomisation: 248 Symdeko, 256 placebo). Patients had a ppFEV1 at screening between 40-90%. The mean ppFEV1 at baseline was 60.0% [range: 27.8% to 96.2%]. In EVOLVE (Study 106) treatment with Symdeko resulted in a statistically significant improvement in ppFEV1 (Table 7). The treatment difference between Symdeko and placebo for the primary endpoint of mean absolute change (95% CI) in ppFEV1 from baseline through Week 24 was 4.0 percentage points (95% CI: 3.1, 4.8; P < 0.0001). Mean improvement in ppFEV1 was sustained throughout the 24-week treatment period (Figure 2). Improvements in ppFEV1 were observed regardless of age, sex, baseline ppFEV1, colonization with Pseudomonas, concomitant use of standard-of-care medications for CF, and geographic region. See Table 7 for a summary of primary and key secondary outcomes.
At Week 24 the proportion of patients who remained free from pulmonary exacerbations was significantly higher for patients treated with Symdeko compared with placebo. The rate ratio of exacerbations through Week 24 in patients treated with Symdeko was 0.65 (95% CI: 0.48, 0.88; P = 0.0054), representing a reduction relative to placebo of 35% (see Figure 1).
BMI increased in both treatment groups in EVOLVE (Symdeko: 0.18 kg/m2, placebo: 0.12 kg/m2). The treatment difference of 0.06 kg/m2 mean change in BMI from baseline to Week 24 (95% CI: -0.08, 0.19) in EVOLVE was not statistically significant.
Symdeko demonstrated improvements in CFQ-R Respiratory Domain (a measure of respiratory symptoms relevant to patients with CF including cough, sputum production, and difficulty breathing) compared to placebo. The treatment difference through Week 24 was 5.1 points (95% CI: 3.2, 7.0). The percentage of subjects with at least a 4 point-increase from baseline was higher in the Symdeko group than in the placebo group at all visits. The odds ratio for Symdeko versus placebo through Week 24 was 2.171 (95% CI: 1.469, 3.208).
EXPAND - a study in patients with CF who were heterozygous for the F508del-CFTR mutation and a second mutation associated with residual CFTR activity (study 108). In the 244 patients enrolled the following indicated mutations associated with residual CFTR activity were represented: 2789+5G→A, 3272-26A→G, 3849+10kbC→T, 711+3A→G, A455E, D110H, D1152H, D579G, E831X, L206W, P67L, R1070W, R117C, R352Q, S945L, and S977F.
EXPAND (Study 108) was a randomised, double-blind, placebo controlled, 2-period, 3-treatment, 8-week crossover study. A total of 244 patients aged 12 years and older (mean age 34.8 years) who were heterozygous for the F508del mutation and a second mutation associated with residual CFTR activity were randomised to and received sequences of treatment that included Symdeko, ivacaftor, and placebo. Patients had a ppFEV1 at screening between 40-90%. The mean ppFEV1 at baseline was 62.3% [range: 34.6% to 93.5%].
In EXPAND (Study 108), treatment with Symdeko resulted in a statistically significant improvement in ppFEV1 (Table 8). The treatment difference between Symdeko- and placebo-treated patients for the primary endpoint of mean absolute change in ppFEV1 from study baseline to the average of Week 4 and Week 8 was 6.8 percentage points (95% CI: 5.7, 7.8; P < 0.0001).
Treatment difference between ivacaftor- and placebo-treated patients was 4.7 percentage points (95% CI: 3.7, 5.8; P < 0.0001) and 2.1 percentage points (95% CI: 1.2, 2.9; P < 0.0001) between Symdeko- and ivacaftor-treated patients. Mean improvement in ppFEV1 was rapid in onset (Day 15) and sustained throughout the 8-week treatment period (see Figure 3). Improvements in ppFEV1 were observed regardless of age, disease severity, sex, mutation class, colonization with Pseudomonas, concomitant use of standard-of-care medications for CF, and geographic region. See Table 8 for a summary of primary and key secondary outcomes.

Subgroup analysis of patients with severe lung dysfunction (ppFEV1 < 40).

EVOLVE and EXPAND included a total of 39 Symdeko-treated patients with ppFEV1 < 40 at baseline (range 30.3, 39.9); 23 patients from EVOLVE and 16 patients from EXPAND. There were 24 placebo treated patients in EVOLVE, and 15 placebo- and 13 ivacaftor-treated patients in EXPAND with ppFEV1 < 40 at baseline. The safety and efficacy in this subgroup were comparable to the overall results observed in both EVOLVE and EXPAND.
Study in patients with CF who were heterozygous for the F508del mutation and a second mutation not responsive to tezacaftor/ivacaftor (study 107). Study 107 was a Phase 3, randomised, double-blind, placebo-controlled, two-arm study that compared Symdeko to placebo in patients with CF aged 12 years and older who were heterozygous for the F508del mutation and had a second CFTR mutation not responsive to tezacaftor/ivacaftor. The primary endpoint of the study was change from baseline in absolute ppFEV1. This study was terminated following the planned interim analysis because the pre-specified futility criteria were met.
EXTEND - a long-term safety and efficacy rollover study (study 110). EXTEND (Study 110) was a Phase 3, open-label, multicenter, rollover, 96-week study to evaluate the safety and efficacy of long-term treatment of Symdeko that included patients from Study 106 (EVOLVE (n = 462)) and Study 108 (EXPAND (n = 227)). Efficacy analyses for Study 661-110 were conducted through 96 weeks. For patients in parent study EXPAND, only the Period 2 treatment assignments were considered in the analysis for EXTEND.
Patients who received placebo in both EVOLVE and EXPAND demonstrated improvements in ppFEV1 when receiving Symdeko in EXTEND. These improvements were observed as early as Day 15 of EXTEND (EVOLVE: within-group change = 3.8 percentage points, EXPAND: within-group change 4.2 percentage points). Patients who received Symdeko in EVOLVE and EXPAND showed sustained improvements in ppFEV1 through 96 weeks in EXTEND [EVOLVE: within-group change=2.1 (95% CI: 0.8, 3.3) percentage points, EXPAND: within-group change=4.1 (95% CI: 2.2, 6.0) percentage points]. Both magnitude and trend of improvement in ppFEV1 observed in EXTEND were similar to those observed for patients who received Symdeko in EVOLVE and EXPAND (see Figure 2 and 3). Similar trends were observed for CFQ-R Respiratory Domain Score as in the parent studies.
Patients who continued on Symdeko from EVOLVE to EXTEND maintained an event rate of pulmonary exacerbations (0.76) that was lower than the placebo event rate per year in EVOLVE (0.99).
Patients who received placebo in EVOLVE and then received Symdeko in EXTEND had a reduction in event rate per year of pulmonary exacerbations from 0.99 to 0.68.
Patients who continued on Symdeko from EXPAND to EXTEND had an event rate of pulmonary exacerbations of 0.22 that was lower than the placebo event rate per year in EXPAND (0.63).
Patients who received placebo in EXPAND and switched to Symdeko in EXTEND had an event rate per year of pulmonary exacerbations (0.44) similar to the event rate observed in Symdeko-treated patients in EXPAND (0.63).
After 96 weeks of Symdeko treatment in EXTEND (Study 110), the absolute change from baseline in BMI for subjects who received placebo in EVOLVE (Study 106) was 0.47 (95% CI: 0.30, 0.65), and for patients who received Symdeko in EVOLVE (Study 106) was 0.38 (95% CI: 0.20, 0.55). After 96 weeks of Symdeko treatment in EXTEND (Study 110), the absolute change from baseline in BMI for subjects who received placebo in EXPAND (Study 108) was 1.07 (95% CI: 0.59, 1.55), for patients who received Symdeko in combination with ivacaftor in Study 108 was 0.96 (95% CI: 0.45, 1.47), and for patients who received Symdeko was 1.05 (95% CI: 0.56, 1.55).
Studies in patients with CF aged 6 to less than 12 years who were homozygous for the F508del mutation or heterozygous for the F508del mutation and a second mutation associated with residual CFTR activity (study 113 Part B (ENTRUST) and study 115 (EMBRACE)). The use of Symdeko in children aged 6-12 years was approved on the basis of partial extrapolation. PK modelling data using studies 113 (Part B) (ENTRUST) and 115 (EMBRACE) showed that the dosing proposed provides an exposure of tezacaftor and ivacaftor similar to that seen in children over 12 years and adults. The sweat chloride and clinical endpoints of studies 113(ENTRUST) (Part B) and 115 (EMBRACE) were supported by studies 106 (EVOLVE) and 108 (EXPAND) in adults.
ENTRUST was a 24-week open label Phase 3 trial in 70 patients aged 6 to less than 12 years. Patients who weighed less than 40 kg received tezacaftor 50 mg/ivacaftor 75 mg and ivacaftor 75 mg and patients who weighed over 40 kg received tezacaftor 100 mg/ivacaftor 150 mg and ivacaftor 150 mg 12 hours apart. At baseline, mean ppFEV1 was 91.1% (range: 63.4%, 118.0%). Patients in ENTRUST were eligible to roll over into a 96-week open label extension study.
EMBRACE was an 8-week, double-blind, Phase 3 trial in 67 patients aged 6 to less than 12 years who were randomized 4:1 to either Symdeko or a blinding group. Blinding groups were placebo, if homozygous for F508del (n=10), or ivacaftor if heterozygous for F508del with a second CFTR allele resulting in residual CFTR function (n=3). Fifty-four patients received either tezacaftor 50 mg/ivacaftor 75 mg and ivacaftor 75 mg (patients weighing < 40 kg at baseline) or tezacaftor 100 mg/ivacaftor 150 mg and ivacaftor 150 mg (patients weighing ≥ 40 kg at baseline), 12 hours apart. The mean baseline ppFEV1 was 86.5% (range: 57.9, 124.1%)]. Patients in EMBRACE were eligible to roll over into a 96-week open-label extension study.
In ENTRUST, secondary endpoints evaluated included absolute and relative change in ppFEV1 from baseline through Week 24 and absolute change in CFQ-R Respiratory Domain Score from baseline through Week 24.
Lung function (ppFEV1) was maintained throughout the 24-week treatment period (mean absolute change from baseline through Week 24 was 0.9 percentage points [(95% CI: -0.6, 2.3]). The mean growth parameters at baseline were close to the mean values for the age-matched general population and remained stable at Week 24.
In EMBRACE, the primary endpoint was absolute within-group change from baseline in LCI2.5 through Week 8 in Symdeko-treated patients. Absolute change from baseline at Week 8 in sweat chloride (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Pharmacodynamic effects, Effects on sweat chloride) and through Week 8 in CFQ-R respiratory domain scores were secondary endpoints. Additional endpoints included LCI5.0, ppFEV1, and growth parameters. Reduction in LCI2.5 was observed at Week 2 and was sustained through Week 8. See Table 9 for results.
In subgroup analyses of F/F and F/RF patients, the within group mean absolute change in LCI2.5 was -0.39 (95% CI: -0.67, -0.10) and -0.92 (95% CI: -1.65, -0.20), respectively. The within group mean change in CFQ-R respiratory domain scores in F/F and F/RF patients was 1.4 points (95% CI: -1.9, 4.7) and 5.6 points (95% CI: -2.8, 13.9), respectively. Growth parameters remained stable over 8 weeks of Symdeko treatment.

5.2 Pharmacokinetic Properties

The pharmacokinetics of tezacaftor and ivacaftor are similar between healthy adult volunteers and patients with CF. Following once-daily dosing of tezacaftor and twice-daily dosing of ivacaftor in patients with CF, plasma concentrations of tezacaftor and ivacaftor reach steady-state within 8 days and within 3 to 5 days, respectively, after starting treatment. At steady-state, the accumulation ratio of tezacaftor is approximately 2.3 for tezacaftor and 3.0 for ivacaftor. Exposures of tezacaftor (administered alone or in combination with ivacaftor) increase in an approximately dose-proportional manner with increasing doses from 10 mg to 300 mg once daily. Key pharmacokinetic parameters for tezacaftor and ivacaftor at steady state are shown in Table 10.

Absorption.

After a single dose in healthy subjects in the fed state, tezacaftor was absorbed with a median (range) time to maximum concentration (tmax) of approximately 4 hours (2 to 6 hours). The median (range) tmax of ivacaftor was approximately 6.0 hours (3 to 10 hours) in the fed state. The AUC of tezacaftor did not change when given with fat-containing food relative to fasted conditions. The AUC of ivacaftor when given in combination with tezacaftor increased approximately 3-fold when given with fat-containing food; therefore, Symdeko should be administered with fat-containing food.

Distribution.

Tezacaftor is approximately 99% bound to plasma proteins, primarily to albumin. Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. After oral administration of tezacaftor 100 mg once daily in combination with ivacaftor 150 mg every 12 hours in patients with CF in the fed state, the mean (±SD) for apparent volume of distribution of tezacaftor and ivacaftor was 271 (157) L and 206 (82.9) L, respectively. Neither tezacaftor nor ivacaftor partition preferentially into human red blood cells.

Metabolism.

Tezacaftor is metabolised extensively in humans. In vitro data suggested that tezacaftor is metabolised mainly by CYP3A4 and CYP3A5. Following oral administration of a single dose of 100 mg 14C-tezacaftor to healthy male subjects, M1, M2, and M5 were the 3 major circulating metabolites of tezacaftor in humans. M1 has similar apparent potency to that of tezacaftor and is considered pharmacologically active. M2 is much less pharmacologically active than tezacaftor or M1, and M5 is not considered pharmacologically active. Another minor circulating metabolite, M3, is formed by direct glucuronidation of tezacaftor.
Ivacaftor is also metabolised extensively in humans. In vitro and in vivo data indicate that ivacaftor is metabolised primarily by CYP3A4 and CYP3A5. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. M6 is not considered pharmacologically active.

Excretion.

After oral administration of tezacaftor 100 mg once daily in combination with ivacaftor 150 mg every 12 hours in patients with CF in the fed state, the mean (± SD) for apparent clearance values of tezacaftor and ivacaftor were 1.31 (0.41) and 15.7 (6.38) L/h, respectively. After steady-state dosing of tezacaftor in combination with ivacaftor in CF patients, the mean (SD) terminal half-lives of tezacaftor and ivacaftor were approximately 156 (52.7) and 9.3 (1.7) hours, respectively.
Following oral administration of 14C-tezacaftor, the majority of the dose (72%) was excreted in the faeces (unchanged or as the M2 metabolite) and about 14% was recovered in urine (mostly as M2 metabolite), resulting in a mean overall recovery of 86% up to 21 days after the dose. Less than 1% of the administrated dose was excreted in urine as unchanged tezacaftor, showing that renal excretion is not the major pathway of tezacaftor elimination in humans.
Following oral administration of ivacaftor alone, the majority of ivacaftor (87.8%) is eliminated in the faeces after metabolic conversion. There was negligible urinary excretion of ivacaftor as unchanged drug.

Hepatic impairment.

Following multiple doses of tezacaftor and ivacaftor for 10 days, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had an approximately 36% increase in AUC and a 10% increase in Cmax for tezacaftor, and a 1.5-fold increase in ivacaftor AUC compared with healthy subjects matched for demographics. Based on these results, a modified regimen of Symdeko is recommended for patients with moderate hepatic impairment (see Section 4.2 Dose and Method of Administration, Table 3).
The impact of severe hepatic impairment (Child-Pugh Class C, score 10-15) on the pharmacokinetics of tezacaftor and ivacaftor has not been studied. The magnitude of increase in exposure in these patients is unknown, but is expected to be higher than that observed in patients with moderate hepatic impairment. Symdeko should be used with caution in patients with severe hepatic impairment (see Section 4.2 Dose and Method of Administration, Table 3).
No dose adjustment is considered necessary for patients with mild hepatic impairment.

Renal impairment.

Symdeko has not been studied in patients with moderate or severe renal impairment (creatinine clearance ≤ 30 mL/min) or in patients with end-stage renal disease. In a human pharmacokinetic study with tezacaftor alone, there was minimal elimination of tezacaftor and its metabolites in urine (only 13.7% of total radioactivity was recovered in the urine with 0.79% as unchanged drug).
In a human pharmacokinetic study with ivacaftor alone, there was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine).
In population pharmacokinetic analysis, data from 665 patients on tezacaftor or tezacaftor in combination with ivacaftor in Phase 2/3 clinical studies indicated that mild renal impairment (N=147; eGFR 60 to 89 mL/min/1.73 m2) and moderate renal impairment (N=7, eGFR 30 to 59 mL/min/1.73 m2) did not affect the clearance of tezacaftor significantly. No dose adjustment for Symdeko is recommended for mild and moderate renal impairment. Caution is recommended when administering Symdeko to patients with severe renal impairment or end-stage renal disease.

Gender.

The pharmacokinetic parameters of tezacaftor and ivacaftor are similar in males and females.

Paediatric population.

Tezacaftor and ivacaftor exposures observed in Phase 3 studies as determined using population pharmacokinetic (PK) analysis are presented by age group (and body weight for patients aged 6 to less than 12 years) in Table 11. Tezacaftor and ivacaftor exposures in patients aged 6 to less than 12 years in Studies 113 Part B (ENTRUST) and 115 (EMBRACE) are within the range of exposures observed in adults.
Pharmacokinetic modeling using data from Studies 113 Part B (ENTRUST) and 115 (EMBRACE) supported the selection of the 30 kg weight cut-off for dosing recommendations in patients 6 to less than 12 years [see Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties, Clinical trials, Efficacy].

5.3 Preclinical Safety Data

Genotoxicity.

Tezacaftor and ivacaftor were both negative for genotoxicity in the following assays: Ames test for bacterial gene mutation, in vitro chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse micronucleus test.

Carcinogenicity.

No evidence of tumourigenicity by tezacaftor was observed in a 6-month study in transgenic (Tg.rasH2) mice and in a conventional 2-year study in rats, conducted by the oral route. The highest doses tested (500 mg/kg/day in mice, 50 mg/kg/day in male rats and 75 mg/kg/day in female rats) yielded exposure to tezacaftor and its M1 and M2 metabolites that was 1.8 fold higher in mice, 1.5-fold higher in male rats, and 2.5-fold higher in female rats than in patients at the MRHD (based on summed AUCs).
Two-year oral studies in mice and rats demonstrated that ivacaftor was not carcinogenic in either species. Plasma exposures to ivacaftor in mice at the non-carcinogenic dosage (200 mg/kg/day, the highest dosage tested) were approximately 5- to 9-fold higher than the plasma levels measured in humans following Symdeko therapy, and at least 1.4- to 2.8-fold higher with respect to the summed AUC for ivacaftor and its major metabolites. Plasma exposures to ivacaftor in rats at the non-carcinogenic dosage (50 mg/kg/day, the highest dosage tested) were approximately 21- to 39-fold higher than the plasma levels measured in humans following Symdeko therapy, and 7- to 11-fold higher with respect to the summed AUC for ivacaftor and its major metabolites.

6 Pharmaceutical Particulars

6.1 List of Excipients

Symdeko tablets (tezacaftor/ivacaftor 50 mg/75 mg or 100 mg/150 mg).

Hypromellose acetate succinate, sodium lauryl sulfate, hypromellose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate.

Film coating.

Symdeko (tezacaftor/ivacaftor 50 mg/75 mg): Opadry complete film coating system 20A180008 White (PI No. 139612).
Symdeko (tezacaftor/ivacaftor 100 mg/150 mg): Opadry complete film coating system 20A120010 Yellow (PI No. 111630).

Ivacaftor tablets (75 mg or 150 mg).

Silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, carnauba wax.

Film coating.

75 mg: Opadry II complete film coating system 85F105098 Blue (PI No. 140157).
150 mg: Opadry II complete film coating system 85F90614 Blue (PI No. 108371), Opacode monogramming ink S-1-17823 Black (PI No. 12108).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine. See Section 4.2 Dose and Method of Administration.

6.3 Shelf Life

In Australia, information on the shelf-life can be found on the public summary of the ARTG. The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.
Store in original container.

6.5 Nature and Contents of Container

Blister consisting of PCTFE (polychlorotrifluoroethylene)/PVC (polyvinyl chloride) with a paper-backed aluminum foil lidding.
Symdeko pack sizes: 56 tablets, monthly pack.
Symdeko (tezacaftor 50 mg/ivacaftor 75 mg) film-coated tablets co-packaged with ivacaftor 75 mg film-coated tablets.
Symdeko (tezacaftor 100 mg/ivacaftor 150 mg) film-coated tablets co-packaged with ivacaftor 150 mg film-coated tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


Tezacaftor: 1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1Hindol-5-yl} cyclopropane-1-carboxamide.
Ivacaftor: N‑(2,4‑di‑tert‑butyl‑5‑hydroxyphenyl)‑4‑oxo‑1,4‑dihydroquinoline‑3‑carboxamide.

CAS number.

Tezacaftor.

1152311-62-0.

Ivacaftor.

873054-44-5.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes